Testing method for a dry powder inhaler

ABSTRACT

The invention provides a method of testing an inhaler based on performing an optical analysis of a dry powder medicament plume discharged from the inhaler upon actuation. More particularly, embodiments of the invention comprise illuminating the dry powder plume with a source of electromagnetic radiation and capturing one or more images of a pattern of radiation reflected or diffracted by the illuminated plume. The images are subsequently processed to determine and/or analyse one or more geometric and/or dynamic characteristics of the plume.

This invention relates to a testing method for a dry powder inhaler(DPI).

Dry powder inhalers (DPIs) represent one class of inhaler used fordelivering inhalable medicament formulations. Other classes of inhalersinclude a pressurised metered dose inhalers (pMDI) and a nebuliser.

The purpose of an inhalable formulation is to present the formulation inthe form of an aerosol of particles having a particle size suitable forlung deposition, which is typically a mass median aerodynamic diameter(MMAD) of 1-5 microns.

pMDIs and nebulisers are generally more efficient than dry powderformulations since approaches which use dry powders tend to suffer fromthe drawback that only a small portion of the powdered active ingredientis actually inhaled into the lungs.

Despite this drawback of lower efficiency, DPIs have the benefit thatthe energy required for aerosolisation of the formulation comes from thepatient's own inhalation. This helps to avoid problems of poorhand-breath coordination (asynchrony) commonly associated withconventional pMDIs (see M. L. Levy et al. Prim Care Respir J. 2013, 22,406-11).

Asynchrony has been observed in up to 58% of patients failing inhalertechnique, and incorrect inhaler use is associated with poor asthmacontrol and an increased risk of exacerbations (see V. Giraud and N.Roche Eur Respir J. 2002, 19, 246-51; H. Al-Jandali et al. AllergyAsthma Clin. Immunol. 2013, 9, 8; and A. S. Sundaresan et al. AllergyAsthma Proc. 2016, 37, 418).

This makes DPIs a useful approach for formulating inhalable activeingredients.

However, further to the known drawbacks described above in terms ofpotential performance and efficiency of DPIs compared with pMDIs andnebulisers, there are also increased difficulties in accurately testingthe performance of DPIs in discharging the powdered medicaments. Inparticular, current methods of testing DPIs are highly limited in thedegree of detail they are able to attain concerning the dynamics andgeometry of the powder medicament plume discharged from the inhaler uponactuation.

The geometry and dynamics of the discharged plume are a significantfactor in assessing the overall performance and efficacy of any inhaler.It may in particular have a substantial impact on the efficiency ofdelivery of medicament to the user.

Present methods for testing the plume characteristics of dry powderinhalers include for example impaction techniques, e.g. an Andersoncascade impactor (ACI) or a next-generation impactor (NGI). Thesetechniques are based on drawing sample laden air through a stackedseries of impaction stages, each comprising a collection surfacedesigned to collect particles of a certain threshold inertia on thesurface, whilst allowing the remainder of the particles to travel on tosuccessive stages via an opening. The air is controlled to progressivelyaccelerate as it travels through the different stages such that eachcollection surface is effectively selecting particles of ever decreasinginertia (i.e. mass). This allows a distribution of particles having agiven inertia to be assessed within a discharged plume. However, thismethod is limited to analysis of the aerodynamic size of the particleswithin the plume and does not give an assessment of the geometric ordynamic characteristics of the plume.

Other methods for testing dry powder inhalers include electrostatictesting in which particles of a discharged dry powder plume are capturedby an electrically charged collection plate, allowing rudimental aspectsof the plume size and range for instance to be estimated. The precisionachievable with such methods however is highly limited, and theattainment for instance of more detailed three-dimensional orcross-sectional analyses is not possible.

Current methods for testing pMDIs and nebulisers allow for high detailphotographic or laser diffraction analysis of the discharged medicamentspray. However these same methods are not directly transferrable to theanalysis of DPIs due to the substantially different physicalcharacteristics of a medicament in a powdered form compared to in anaerosolised form.

Absence of comparable plume characteristic data for dry powder inhalersis inhibiting efficient optimisation of these devices, since the impactupon powder discharge behaviour of any fine precision adjustments to theinhaler design is difficult to determine.

There is a need therefore for improved methods for testing dry powderinhalers to enable more detailed analysis of the characteristics of thedischarged medicament powder plume.

Accordingly, the present invention provides a method of testing a drypowder inhaler comprising the steps of:

providing a dry powder inhaler (20) containing a dry powder formulation;actuating the inhaler to discharge a dose of the dry powder formulationin the form of a dry powder plume (24);

illuminating the plume with a source of electromagnetic radiation (28);

capturing one or more images of a pattern of radiation reflected ordiffracted by the electromagnetically illuminated plume (24); and

processing the images to determine one or more geometrical and/ordynamical characteristics of the discharged plume (24).

The present invention will now be described in detail with reference tothe accompanying drawings, in which:

FIG. 1 schematically depicts an example testing method in accordancewith the invention to obtain a longitudinal view of a discharged powderplume;

FIG. 2 schematically depicts a further example testing method inaccordance with the invention to obtain a cross-sectional view of adischarged powder plume;

FIG. 3 schematically depicts the distal end of an airflow adaptor of anexample inhaler tested in accordance with the present invention;

FIG. 4 schematically depicts the proximal end of an airflow adaptor ofan example inhaler tested in accordance with the invention;

FIG. 5 schematically depicts a further view of the airflow adaptor ofthe example inhaler tested in accordance with the invention;

FIG. 6 schematically depicts a deagglomerator including a swirl chamberbypass port of the example inhaler tested in accordance with theinvention;

FIG. 7 schematically depicts an isometric view of the example inhalertested in accordance with the present invention;

FIG. 8 shows a cross-sectional view of the example inhaler tested inaccordance with the invention;

FIGS. 9-12 show an image of a powder plume captured in accordance withthe invention; and

FIGS. 13-16 show an image of a cross-section of a powder plume capturedin accordance with the invention.

The invention provides a method of testing an inhaler based onperforming an optical analysis of a dry powder medicament plumedischarged from the inhaler upon actuation. More particularly,embodiments of the invention comprise illuminating the dry powder plumewith a source of electromagnetic radiation and capturing one or moreimages of a pattern of radiation reflected or diffracted by theilluminated plume. The images are subsequently processed to determineand/or analyse one or more geometric and/or dynamic characteristics ofthe plume.

Implementations of the invention allow for highly detailed informationto be obtained on the discharge behaviour of the inhaler, informing forinstance future improvements to the design or to the way in which theinhaler is to be used. The invention thus provides a contribution to themore overarching technical aim of achieving improvements in inhalerdesign and fluid dynamical performance.

The invention is based on capturing images of a pattern of radiationreflected or diffracted by the illuminated plume. By this is meantcapturing an image of the reflection or diffraction pattern cast by theplume upon illumination by the source of electromagnetic (EM) radiation.Capturing an image of the reflection pattern may simply correspond withcapturing an image of the illuminated plume.

Geometrical characteristics means characteristics pertaining to theshape or dimensions of the plume. Geometrical characteristics mayinclude, but are not limited to, a length of the plume, a width of theplume, a cross-sectional area of the plume at a particular distancealong its length and/or the cross-sectional area as a function ofdistance along the plume length, as well as powder density orconcentration distribution across the plume volume.

Dynamical characteristics means characteristics pertaining to thedynamics or mechanics of the plume as a physical system. Dynamical isintended to be understood synonymously with dynamic. Dynamicalcharacteristics may include, but are not limited to, an envelopevelocity of the plume (i.e. a velocity of the plume, taken as a whole),a direction of movement of the plume, a dispersion rate of the plume,and particle velocities within the plume.

FIGS. 1 and 2 schematically depict execution of respective first andsecond example testing methods in accordance with the invention.

FIG. 1 shows execution of an example testing method configured forcapturing and analysing characteristics of a discharged plume as viewedalong a longitudinal axis 42 of the plume. An example inhaler 20 isactuated to discharge from a mouthpiece 22 a dose of medicament in theform of a dry powder plume 24. The plume is schematically depicted inFIG. 1 by means of a triangle representing a general shape of an outerenvelope of the plume. Axis 42 represents a central axis of the outerenvelope shape of the plume, indicating an axis of orientationalalignment or directionality.

Outer envelope means the outer profile (i.e. outline) of the plume,taken as a whole. The central axis defines a line of directionality ofthe plume in the sense of a direction in which the powder plume is,taken as a whole, moving. Accordingly, the outer envelope shape of thedischarged plume 24 has a central axis 42 defining an angularorientation of the discharged plume, and wherein the method comprisesanalysing said angular orientation of the plume. Thus, the presentinvention also comprises analysing a cross-sectional area 44 of an outerenvelope shape of the discharged plume 24 at a given distance from asource of discharge of the plume, and optionally wherein said source ofthe discharge is defined as a distal end of a mouthpiece 22 of theinhaler 20.

Upon actuation of the inhaler 20 and discharge of the dry powder plume24, a laser 28 is controlled to direct a laser light output 32 (i.e. EMradiation) onto the discharged power plume 24. In the present example,the laser light output is generated or optically processed so as toprovide a spatially expansive or diverging beam (spatially extended inone or both dimensions orthogonal to a propagation direction) across theplume in the form of a sheet of light. Such an extended light sheet mayenable a large region (or even the totality) of the plume to beilluminated and accordingly imaged for analysis. In particular examples,the laser 28 may be a FireFLY laser.

The laser 28 may be a visible light laser or may be a non-visible lightlaser such as for instance an infrared laser, ultraviolet laser, X-raylaser, or gamma-ray laser. The term should also be understood ascovering masers.

Although a laser light source 28 is provided in the particular exampleof FIG. 1, it is to be understood that in this or any other example, thelight source may be replaced by any suitable source of electromagneticradiation. This may comprise a source of visible light or may be asource of a different form of electromagnetic radiation, such asinfrared, microwaves, ultraviolet, x-rays or gamma rays for instance.Accordingly, the term images is to be construed broadly, as encompassingimages formed through illumination by radiation of any region of theelectromagnetic spectrum.

Concurrently with discharge and illumination of the dry powder plume 24,a high speed camera 36 is controlled to capture a plurality of images insuccession of the pattern of laser light reflected or diffracted by theilluminated plume. The images are preferably captured as a plurality ofimages in series. The camera 36 may be configured to capture imagesrecurrently at a frequency of 500 Hz for example. The images may becaptured using high-speed photography techniques.

By capturing a plurality of images at regular intervals, details on thedynamics of the plume can be derived, including for instance internaldynamics of the particles within the plume as well as the dynamics ofthe overall plume itself, e.g. velocity, acceleration, dispersion rate.

Increased frequency in the image capturing leads to a greater detail inthe obtainable analysis of the plume dynamics. Higher frequencies aretherefore typically preferable. In particular examples, the images maybe captured at regular intervals at an interval frequency of from 300 to1,000 Hz

In preferred examples, the images are captured at a frequency of atleast 500 Hz. It has been found by the inventors that an image capturefrequency of at least 500 Hz provides a particularly beneficial balancebetween high detail in the dynamical analysis while not placing overlyhigh demand upon any computing resources required to process the images.

The camera 36 may be configured to capture diffraction patternsgenerated by illumination of the particles of the plume 24 by the laserlight 32. In this case, the method may be a form of laser diffractiontechnique, wherein the pattern of diffraction generated by the plume iscaptured in an image and used to determine or analyse the geometricaland/or dynamic properties of the plume, including for instance densityor concentration distribution.

Axis 40 illustrates a direction of focus of the camera 36, for instancethe axis extending normally with respect an imaging plane of the camera.In this example, configured for capturing a longitudinal view of thedischarged dry powder plume 24, the axis of focus of the camera isoriented approximately perpendicularly with respect to the axis oforientation (central axis) 42 of the plume 24.

Although a high speed camera is provided for capturing images in theparticular example of FIG. 1, in further examples any suitable form ofimage capture device may be used which for instance comprises one ormore elements sensitive to the respective band of the electromagneticspectrum used to illuminate the plume. This may be a non-high-speedcamera or a different variety of photosensitive device for instance. Adevice specifically configured for capturing diffraction patternsgenerated by laser illumination of the particles of the plume may alsobe used for instance.

Upon capturing the images, the images are processed to thereby determineand analyse one or more geometric and/or dynamic characteristics of theexamined dry powder plume 24. This analysis may be performed bydedicated analysis software executed on a suitable computer device.Alternatively a dedicated image processor may be used to process theimages and output analysis results.

Processing of the images of the longitudinal view of the powder plumecaptured in the method of FIG. 1 may typically enable determination (foreach image) of at least: the orientation of the plume central axis 42(relative to a given reference axis, such as an axis of a portion of theinhaler 20, or an absolute horizontal or vertical axis for instance),the angle of the cone defined by the plume outer envelope, the width ofthe plume at different points along its longitudinal length, and alength of the plume.

The central axis can be derived by finding a line which defines a medianpoint across the width of the captured plume pattern.

The angle of the cone defined by the plume outer envelope (the angularextent of the cone) can be derived by finding the angular displacementbetween two lines defining the angular boundaries of the plume. Theseangular boundary lines might be chosen for instance so that a certainminimum percentage of the total plume area or captured volume is withinthe lines, e.g. 90%.

The plume width may be defined as a linear distance between these twoboundary lines.

The method may comprise determining an angle of deviation of the centralaxis 42 of the discharged plume 24 with respect to an axis oforientation of the mouthpiece 22, i.e. the axis extending parallel to aninner conduit defined by the outer walls of the mouthpiece.

This angle of deviation may be a relevant factor in the performance orefficiency of the device. For instance if the angle of deviation of theplume 24 is particularly high, this may mean that the medicament isbeing incorrectly directed, for instance downward into the throat ratherthan directly along the airway for delivery to the lungs. Thisinformation may be used for instance to refine the design in the futureor to change the way the device is used or configured. Accordingly, thedry powder inhaler 20 preferably comprises a mouthpiece 22, and whereinthe method comprises determining an angle of deviation of said centralaxis 42 of an outer envelope of the discharged plume 24 with respect toan axis of orientation of the mouthpiece.

The processing of the images and generation of analysis data may beperformed simultaneously with capturing of the images or alternativelymay be performed subsequently.

Processing of the images to thus derive indications or measures of thegeometrical or dynamical characteristic(s) can be performed using anysuitable image analysis procedure. This may be computer implemented, forinstance by means of image analysis software executed on a computer.Alternatively it may according to further examples be implemented by asuitable image processor.

Oxford Lasers Envision Patternate software is one example of suitablesoftware which may be used to extract plume geometry and dynamicsinformation from the captured images. The software can be purchased fromOxford Lasers.

The Oxford Lasers EnVision Patternate software enables extraction fromcaptured images of at least the following characteristics: plume coneangle, plume width, plume height, spray pattern ellipticity, spraypattern size, and spray event duration.

The EnVision software performs characterisation on a single image or cancombine a sequence of images of the plume to form a composite image andthen measures the cone angle, direction, plume geometry and otheruser-definable parameters.

A further piece of software which may in accordance with examples beused to extract plume geometry and dynamics information from thecaptured images is Oxford Lasers VidPIV software. This software may bepurchased from Oxford Lasers.

The Oxford Lasers VidPIV software permits extraction in particular ofplume velocity information, and allows an average velocity of the plumeto be derived, as well as a full velocity vector map of the plume overtime.

The obtained set of consecutive images may be processed to form acomputational fluid dynamical model of the plume. This may be used toprovide highly detailed information on a range of aspects of the plumebehaviour throughout the duration of the discharge process including forinstance aspects of its geometry, density and mechanics at differentmoments in time, as well as how these properties change as a function oftime.

In particular examples, the inhaler 20 may be actuated in a vacuumchamber or an air flow chamber. This may improve accuracy or detail ofthe obtained analyses of plume geometry or dynamics. By conducting thetest in a vacuum, the plume is unaffected by environmental (fluid)conditions for example.

FIG. 2 shows execution of an example testing method of the invention,configured for capturing and analysing characteristics of a dischargedplume 24 across a given cross-section 44 at a given distance from asource of discharge of the plume. As in the example of FIG. 1, a testinhaler 20 is actuated to discharge a dose of medicament in the form ofa dry powder plume 24. Again, the plume is illustrated schematically bya triangle shape, representing an outer envelope shape of the plume.Axis 42 represents a central axis of the envelope shape, and indicates ageneral angle of orientation of the plume 24. All terms may beunderstood as defined above.

Upon actuation of the inhaler 20 and discharge of the plume 24, a laser28 is controlled to direct a source of laser light 32 across at least aparticular cross-sectional region 44 of the illuminated plume 24 at agiven distance from a source of discharge of the plume (in this case adistal end of the mouthpiece 22). The given distance may be selected inadvance, typically 3 cm or 6 cm. In particular examples, the distancemay be 3 cm. Testing at this distance is standard within the field ofinhaler testing.

As in the example of FIG. 1, the light output 32 of the laser 28 may begenerated or optically processed so as to provide an approximatelyplanar sheet of light. This may be directed (as shown in FIG. 2)radially across the width of a particular cross-sectional region 44 ofthe plume 24.

Concurrently with discharge and illumination of the plume 24, ahigh-speed camera 36 is controlled to capture a series of images inquick succession (for instance at a frequency of at least 500 Hz). Axis40 indicates a direction of focus of the camera 36. In this particularexample, configured for capturing a cross-sectional view or impression(e.g. as created by a diffraction pattern) of the plume 24, the imagingplane of the camera is aligned in parallel with the direction oforientation (as indicated by central axis 42) of the dry powder plume24. This enables the camera to capture the reflection or diffractionpattern cast by the particular cross-section 44 of the plume beingilluminated by the laser 28.

As in the previous example, use of a high-speed camera is indicated forthe particular example illustrated in FIG. 2. However, this is notessential, and in further examples any suitable image or light patterncapturing device may be used. A device configured specifically forcapturing diffraction patterns may for instance be used in accordancewith one or more examples.

Upon capturing the images, the images are processed to thereby determineand analyse one or more geometric and/or dynamical characteristics ofthe dry powder plume 24. This analysis may be performed by dedicatedanalysis software executed on a suitable computer device. Alternativelya dedicated image processor may be used to process the images and outputanalysis results. Suitable example software is described above.

Processing of the images of the cross-sectional view 44 of the powderplume 24 captured in the method of FIG. 2 may typically enabledetermination of (for each image) at least: a radius of the plume crosssection in each angular direction, maximal and minimal dimensions of theplume cross-section, a total area of the cross-section, and aconcentration (or density) distribution of the powder across thecross-section 44.

The cross-sectional area of the plume may provide an indication ofdeagglomeration performance of the inhaler. For example, a smallercross-section may typically indicate a greater average powder densitywithin said cross-section 44. Where there is a greater density ofpowder, there is typically a greater rate of inter-particle collisionswhich lead to break-up (i.e. deagglomeration) of agglomerations of thepowder medicament. For best medical results, it is preferable that thepowder contains a high percentage fine particle fraction. Hence, byanalysing cross-sectional area, an indication of post-dischargedeagglomeration performance is attainable.

The cross-sectional area may also be relevant for other reasons. Forinstance, a narrower cross-section may in particular cases be preferablefor instance to provide more directional discharge of the powder into auser's airway. A wider or more dispersed plume may for instance be moreprone to spreading into the user's throat or mouth.

The concentration distribution of the powder may provide informationrelevant to the medical efficiency of the device. For example, a greaterconcentration of particles at a more central region may indicate a moredirectionally focussed plume. For instance, a plume having a highcentral concentration may be less prone to substantial radial dispersionas it travels toward the user's airway.

Additionally, a more centrally concentrated plume may exhibit greaterdeagglomeration action after discharge from the inhaler due to increasedparticle interactions.

Powder concentration distribution means powder density distributionacross the given cross-section 44. By this is not meant the density ofthe material itself, but rather the concentration of the powder, i.e.the number of powder particles per unit area, as a function of positionacross the cross-section in question. The concentration distribution maybe in the form of a set of values of powder density or concentration atdifferent points across the imaged cross-section 44. Thus, the presentinvention comprises determining a powder concentration distributionacross a given cross-section 44 of the discharged plume 24 at a givendistance from a source of discharge of the plume.

In accordance with one or more examples, a number of differentcross-sections 44 may be imaged at different distances from themouthpiece 22, and in these cases, the processing of the images mayenable determination of the above properties for each of the imagedcross-sections.

The processing of the images and generation of analysis data may beperformed simultaneously with capturing of the images or alternativelymay be performed subsequently.

Methods for processing the images to derive these properties have beendescribed above.

It is to be noted that any features or possible variations described inrelation to one of the two examples (of FIG. 1 and FIG. 2) are to beunderstood as equally applicable to the other of the two examples.Features of each may be combined or exchanged to provide furtherexamples.

Benefits of the testing method of the present invention in providinginstructive analysis of the geometric and dynamic characteristics of thegenerated powder plume may become more apparent through examination of aparticular example of its application.

One example of the use of the method will now be described in detail, inrelation to a particular example inhaler device tested in accordancewith the method. A brief outline of the features and characteristics ofthe inhaler tested will first be presented, before describing theresults of testing. A more detailed description of the particularinhaler tested may be found in WO 2011/054527.

The inhaler tested is a breath-actuated dry powder inhaler comprising anairflow adaptor, the airflow adaptor comprising: a first conduit havinga proximal end and a distal end, wherein the proximal end allows fluidcommunication from a deagglomerator outlet port to the distal end of theconduit, and wherein the airflow adaptor further comprises at least onesecond conduit for allowing air to flow from a proximal end of theadaptor to a distal end of the adaptor independently of the airflow inthe conduit when a breath induced low pressure is applied to the distalend of the airflow adaptor. Furthermore, the ratio of the sum of thecross-sectional areas of the at least one second conduit to thecross-sectional area of the first conduit is such that when a breathinduced low pressure is applied to the distal end of the airflow adaptorfrom about 20% to about 50% of the resulting airflow is through the atleast one second conduit.

The at least one second conduit of the airflow adaptor hence allows airto by-pass the deagglomerator, thereby altering the dynamics of thegenerated powder plume.

FIG. 3 shows a distal end of the airflow adaptor 100. The airflowadaptor comprises a conduit 101 with a first circumferential flange 106.

The airflow adaptor also comprises means for allowing air to flow from aproximal end of the adaptor to a distal end of the adaptor independentlyof the airflow in the conduit when a breath induced low pressure isapplied to the distal end of the airflow adaptor. The means for thusallowing air to flow independently of the conduit are in the form offour apertures 102, 103, 104, 105 in the first circumferential flange106. In alternative embodiments there may be other numbers of apertures.

FIG. 4 shows a view of the proximal end 201 of the airflow adaptor 200in a partially constructed state. The airflow adaptor comprises aconduit 202 with a first circumferential flange 203. The conduit shownhas a circular cross-section; however, it may have any cross-sectionalshape.

The airflow adaptor also comprises means for allowing air to flow from aproximal end of the adaptor to a distal end of the adaptor independentlyof the airflow in the conduit when a breath induced low pressure isapplied to the distal end of the airflow adaptor. The means are in theform of four apertures 204, 205, 206 (fourth not shown) in the firstcircumferential flange 203. Other numbers of apertures may also beprovided.

The airflow adaptor 200 shown in FIG. 4 further comprises a secondcircumferential flange 208. The second circumferential flange alsocomprises four apertures 210, 211, 212 (fourth not shown).

The proximal end 209 of the conduit 202 allows fluid communication froma deagglomerator outlet port to the distal end of the conduit. Inparticular, the airflow adaptor 200 shown in FIG. 4 has a mating surface214 for mating with the outlet port of a deagglomerator outlet port.Preferably, they mate such that, during use, air will not flow acrossthe mating surface. In certain other embodiments, the outlet port andthe airflow adaptor may be a unitary structure.

FIG. 5 shows a view of the proximal end 301 of the airflow adaptor 300in a fully constructed state. In this figure, four second conduits 304,305, 306 (fourth not shown) can be seen, running from the secondcircumferential flange 308 to the first circumferential flange 303.These provide means for allowing air to flow from a proximal end of theadaptor to a distal end of the adaptor independently of the airflow inthe conduit when a breath induced low pressure is applied to the distalend of the airflow adaptor

The airflow adaptor may be moulded from any suitable polymeric material,including for instance polypropylene and acrylonitrile butadienestyrene.

FIG. 6 shows a deagglomerator 500 coupled with the airflow adaptor 501.The deagglomerator 500 comprises: an airflow adaptor 501 providing fluidcommunication between the outlet port 530 and a region exterior to thedeagglomerator; an inner wall 512 defining a swirl chamber 514 extendingalong an axis B from a first end 518 to a second end 520; a dry powdersupply port 522 in the first end 518 of the swirl chamber 514 forproviding fluid communication between a dry powder delivery passagewayof an inhaler and the first end 518 of the swirl chamber 514; at leastone inlet port 524, 525 in the inner wall 512 of the swirl chamber 514adjacent to the first end 518 of the swirl chamber 514 providing fluidcommunication between a region exterior to the deagglomerator and thefirst end 518 of the swirl chamber; an outlet port 530 providing fluidcommunication between the second end 520 and the airflow adaptor 501;and at least one swirl chamber bypass port 502, 503, 504, 505.

The at least one swirl chamber by-pass port 502, 503, 504, 505 allowsair to flow (shown by arrows labelled 5) from a proximal end of theairflow adaptor to a distal end of the airflow adaptor 501 independentlyof the swirl-chamber 514 when a breath-induced low pressure is appliedto the distal end of the airflow adaptor. The breath induced lowpressure at the distal end of the airflow adaptor 501 also causes air toflow into the swirl chamber 514 through the dry powder supply port 522and the at least one inlet port 524, 525. The combined airflow (arrow 4)leaves the airflow adaptor 501 through the conduit 507 (shown by arrow6).

The at least one swirl chamber bypass port shown in FIG. 6 is in theform of four apertures 502, 503, 504, 505 in a first circumferentialflange 506 of a conduit 507 of the airflow adaptor 501. The airflowadaptor 501 shown in FIG. 6 further comprises an optional secondcircumferential flange 508 which also comprises four apertures 509, 510,511 (fourth not shown). When present, in use, the apertures 509, 510,511 (fourth not shown) in the second circumferential flange 508 alsoform part of the swirl chamber bypass port.

The airflow adaptor shown in FIG. 6 is the airflow adaptor shown in FIG.5. The second conduits of FIG. 5 perform the function of swirl chamberbypass ports. Indeed any of the airflow adaptors described herein whencombined with a deagglomerator as described above provide a swirlchamber bypass port.

The ratio of the sum of the cross-sectional areas of the at least oneswirl chamber bypass ports to the cross-sectional area of outlet port issuch that that when a breath induced low pressure is applied to thedistal end of the airflow adaptor from about 20% to about 30% of theresulting airflow is directed through the at least one swirl chamberbypass port.

FIG. 7 shows the external appearance of the breath-actuated dry powderinhaler 600 tested. The breath-actuated dry powder inhaler comprises anairflow adaptor 601 having a conduit 602 and four second conduits 603,604, 605, 606. In this instance, the conduit 602 and the second conduits603, 604, 605, 606 have circular cross-sections.

FIG. 8 shows the breath-actuated dry powder inhaler 700 comprising thedeagglomerator 701 and the airflow adaptor 702.

The airflow adaptor 702 comprises a conduit 703 with a firstcircumferential flange 704 comprising four apertures (not shown). Theairflow adaptor further comprises a second circumferential flange 705also comprising four apertures (not shown). The apertures in the firstand second circumferential flanges perform the function of swirl chamberbypass ports (by performing the function of the at least one secondconduit(s)). Accordingly, in use, a breath-actuated low pressure at thedistal end 706 of the airflow adaptor 702 causes air to flow through theapertures (not shown) in the first 704 and second 705 circumferentialflanges. The breath-actuated low pressure at the distal end 706 of theairflow adaptor 702 also causes air to entrain medicament and deliver itto the swirl chamber 707 via a supply port.

The above described inhaler (henceforth referred to as a ‘high-flowinhaler’) has been tested using an embodiment of the testing method ofthe present invention. For comparison, a second inhaler (henceforthreferred to as a ‘standard inhaler’) was also tested, this being similarto the first except that the airflow adaptor does not comprise the foursecond conduits 603, 604, 605, 606 acting as swirl chamber by-passconduits. Accordingly, when a breath induced low pressure is applied tothe distal end of this second inhaler's airflow adaptor, all of theresulting airflow is directed through the swirl chamber.

Each of the two inhaler varieties was tested using each of the twoexample methods described above (with reference respectively to FIGS. 1and 2). In each case, two randomly selected sample inhalers of thatvariety were tested in accordance with the particular method concerned.

FIGS. 9 and 10 show plume pattern images captured for each of two samplestandard inhalers (i.e. without the by-pass conduits) tested inaccordance with the longitudinal view test illustrated in FIG. 1.

Table 1 below sets out a summary of the results achieved for these twotests. In particular, the table details average values for anorientation of the discharged plume (i.e. orientation angle of a centralaxis of the plume) relative to the mouthpiece of the inhaler, as well ascone angle of the outer envelope shape of the plume and total length andwidth of the plume. The mouthpiece in this case was oriented with itsoutflow aligned horizontally.

TABLE 1 Longitudinal view test results for standard inhaler OrientationCone Angle Cone width (cm) at 3 Length (°) (°) cm from mouthpiece (cm)Average 104.96 35.72 1.57 10.65 SD 0.71 1.85 0.2 0.66

The results of the test reveal some surprising features of thedischarged plume geometry. In particular, it can be seen from both FIGS.9 and 10 and from the values in Table 1 that despite the horizontalalignment of the mouthpiece, the discharged plume is oriented with adownward incline. It was expected by the inventors that the test wouldreveal that the plume was emitted approximately horizontally, with anydrop being commensurate only for example with the effects of gravity.However, the results reveal a significant declination of the plumealignment. In particular, average angle of a central axis of the plumewith respect to vertical was found to be 104.96° (where 90° would haveindicated perfect horizontal alignment). There is hence a misalignmentin this case of approximately 15°.

Such an angular misalignment may have tangible effects on the medicalefficiency of the inhaler in delivering the powdered medicament. Forexample, a greater angle of deviation may lead to less efficientdelivery of the medicament to a user's airway, for instance by allowingsome of the powder to be misdirected to undesired areas such as thethroat or mouth.

The results for the standard inhaler may be compared with those achievedfor the high-flow inhaler. FIGS. 11 and 12 show plume pattern imagescaptured for each of two example high-flow inhalers (i.e. with theby-pass conduits) and Table 2 below sets out a summary of the resultsachieved for these two tests. The same quantities were measured as inthe above described tests for the standard inhalers and, again, themouthpiece was oriented with its outflow aligned horizontally.

TABLE 2 Longitudinal view test results for the high-flow inhalerOrientation Cone Angle Cone width (cm) at 3 Length (°) (°) cm frommouthpiece (cm) Average 97.73 33.52 1.41 11.18 SD 1.91 1.94 0.08 0.17

It is apparent both from the captured images shown in FIGS. 11 and 12and from the numbers in Table 2 that the plume characteristics for thehigh-flow inhaler are significantly different to those for the standardinhaler.

In particular, the angle of orientation of the plume for the high-flowinhaler is closer to horizontal. The average angle of the central axisof the plume from vertical was found to be 97.73°, i.e. deviating onlyapproximately 8° from perfect horizontal alignment. This hencerepresents a reduction of approximately 7° in the angle of deviation ofthe plume from horizontal compared with the standard inhaler.

This hence provides an indication that the structural differencesbetween the two varieties of inhaler significantly impact upon theirfluid dynamical performance. It can be inferred from these tests inparticular that the presence of the by-pass ports of the high-flowinhaler (described above in relation FIGS. 3-8) reduces the angle ofdeviation of the discharged powder plume from perfect horizontalalignment. Such results, achievable using the methods of the presentinvention provide a tangible technical contribution to the overalltechnical object of improving fluid dynamical performance and/or medicalefficacy of inhalers.

Other results obtained using the longitudinal view tests are alsonotable. It may be seen for instance that the cone angle of the plume issmaller for the high-flow inhaler (at an average of 33.52°) than for thestandard inhaler (having an average of 35.72°). This indicates that thestructural differences in the high-flow inhaler also lead to a narroweror more focussed plume (something also revealed more clearly in thecross-sectional view tests, results of which are described below).

As noted above, a more focussed or less dispersed plume may havetangible effects on efficiency or performance of the inhaler, forinstance enabling greater directionality of the plume, thereby allowingeasier targeting of the powdered medicament directly toward the airwayof the user, and potentially limiting misdirecting of the medicamentinto the throat or mouth. A more focussed plume may also increaseso-called post-discharge deagglomeration action, wherein aparticle-particle collision rate within the plume after ejection fromthe inhaler is increased due to the greater plume density. This leads tofurther deagglomeration of the powder, which improves medical efficacyof the medicament once delivered.

The reduction of cone angle is also reflected in the results for plumewidth for the respective Inhaler varieties, with the average plume widthreducing from 1.57 cm (for the standard inhaler) to 1.41 cm (for thehigh-flow inhaler).

FIGS. 13 and 14 show plume pattern images captured for each of twoexample standard inhalers (i.e. without the by-pass conduits) tested inaccordance with the cross-sectional view test illustrated in FIG. 2. Theimages capture a cross-section of the discharged plume at a distance of3 cm from the inhaler mouthpiece Table 3 below details the numericalresults for these tests, in particular setting out average values for arange of dimensional characteristics of the particular cross-sectionimaged.

TABLE 3 Cross-sectional view test results for standard inhaler Orienta-Orienta- Length of tion of Length of tion of shortest shortest longestlongest Min/ diameter diameter diameter diameter max Area (cm) (°) (cm)(°) ratio (cm²) Average 2 62.02 3.72 37.08 1.87 6.16 SD 0.22 11.76 0.2510.25 0.22 0.54

Two particularly notable results are those of total cross-sectional area(with an average value of 6.16 cm²) and length of the longest diameterof the cross-section (average value of 3.72 cm).

These results are notable by comparison with the corresponding resultsobtained for the high-flow inhaler. FIGS. 15 and 16 show plume patternimages captured for two example high-flow inhalers tested in accordancewith the cross-sectional view test of FIG. 2. The images againcorrespond to cross-sections at a distance of 3 cm from the inhalermouthpiece. Table 4 below details the average numerical results for thetwo tests.

TABLE 4 Cross-sectional view test results for high-flow inhaler Orienta-Orienta- Length of tion of Length of tion of shortest shortest longestongest Min/ diameter diameter diameter diameter max Area (cm) (°) (cm)(°) ratio (cm²) Average 1.93 59.78 2.97 31.03 1.55 4.51 SD 0.21 15.560.17 14.98 0.08 0.59

It can be seen both from the images and Tables 3 and 4 that the averagecross-sectional area for the high-flow inhalers is significantly lessthan the corresponding areas for the standard inhalers. In particular,the average area for the high-flow inhaler plumes decreases to 4.51 cm²compared to an average value of 6.16 cm² for the standard inhaler. Thisdecrease in size of the cross-section is also reflected in the value forthe length of longest diameter, which has an average value of 2.97 cmfor the high-flow inhaler compared to 3.72 cm for the standard inhaler.

The smaller cross-sectional area for the high-flow inhaler may indicatea more concentrated or focussed plume. As noted above, this may alsoindicate a greater directionality of the plume, allowing for moreefficient delivery of the powdered medicament to the user's airway, ormay indicate increased post-discharge deagglomeration action.

In addition to the reduced cross-sectional area, another notable resultis that of concentration distribution of the powder across the imagedcross-section. This property is reflected in the full-colour originalimages by a colour variation across the imaged cross-section(information not visible in the black-and-white versions of the imagesprovided herein).

However, the colour distribution shows that for the high-flow inhalerplume, there is a significantly elevated powder density (orconcentration) within a central region of the plume cross-sectioncompared to more extremal regions. This indicates a more centrallyfocussed or concentrated plume, with central regions comprising agreater concentration of powder than outer regions.

This contrasts with the equivalent result for the standard inhaler,where the colour distribution, although indicating some elevated powderconcentration within central regions, reveals a comparatively homogenouspowder concentration distribution across the cross-section imaged.

It is to be noted that although the example testing method above isdescribed specifically in relation to testing of two varieties ofinhaler in particular, this is purely by way of illustration, and is notto be understood an implying any limitation on the scope ofapplicability of the testing method to any alternative dry powderinhaler.

It can be seen that example testing methods of the present inventionenable technically relevant information concerning characteristics ofthe discharged medicament plume to be obtained. The results of thistesting may furthermore be utilised in modifying or refining the designof an inhaler. By comparing results for two designs, it may be seen thata particular distinguishing feature or modification of one design leadsto an advantageous effect upon the geometric or dynamicalcharacteristics of the plume. These results may then be utilised infurther design procedures to improve the design.

Accordingly, the present invention also provides a method of designing adry powder inhaler 20, the inhaler being operable to discharge a dose ofmedicament in the form of a dry powder plume, the method comprising:

providing a first dry powder inhaler in accordance with a first design,the design intended to achieve a particular desired set of plumegeometric and/or dynamic characteristics;

testing the dry powder inhaler 20 by means of a testing method definedin any preceding claim; and

if necessary, adjusting the design of the first dry powder inhaler 20based on results of said testing so as to better achieve the desired setof plume geometric and/or dynamic characteristics.

In particular, the method may comprises adjusting the design so as tominimise an angle of deviation of a central axis 42 of an outer envelopeshape of the discharged plume 24 with respect to an axis of orientationof a mouthpiece 22 of the inhaler, and optionally wherein the mouthpiecedefines a source of discharge of the plume. The mouthpiece may define asource of discharge of the plume.

As noted above, a large angle of deviation may be medicallydisadvantageous, leading to delivery of the powder to regions where itis not required, such as the throat or mouth. By minimising this angle,such deficiencies in the performance of the device may be ameliorated.

Additionally or alternatively, the method may comprise adjusting thedesign so as to reduce a cross-sectional area 44 of an outer envelopeshape of the discharged plume 24 at a given distance from a source ofdischarge of the plume.

As noted above, reducing the cross-section may increase deagglomerationaction within the plume as it exits from the inhaler. This leads tofiner breakdown of the powder and improved medical efficacy. Reducingthe cross-section may also enable greater directionality in theprojected plume, allowing for more focussed delivery of the powerdirectly into the airway of the user.

The method may, additionally or alternatively, comprise adjusting thedesign so as to alter a concentration distribution of the powder acrossa given cross-section of the plume, the cross-section being located at agiven distance from a source of discharge of the plume. In particularexamples, the design may be adjusted so as to increase a concentrationof the powder within a central region of the cross section, proximal toa central point or centroid of the cross section.

As noted above, increased concentration within a central region mayimprove medical efficacy, for example by rendering a more directionallyfocussed plume, or by increasing post-discharge deagglomeration actionwithin the plume.

By way of more particular illustration, the example test resultspresented above in respect of the standard and high-flow inhalers mightbe utilised in example design methods to refine a design of an inhalerin accordance with the distinguishing features of the high-flow inhalerwhich were found to lead to advantageous alterations in thecharacteristics of the inhaler plume.

In particular, there may be provided in accordance with one or moreaspects of the invention, a method of designing a dry powder inhalerwherein the dry powder inhaler is a breath-actuated dry powder inhalercomprising an airflow adaptor, the airflow adaptor comprising:

a first conduit having a proximal end and a distal end, wherein theproximal end allows fluid communication from a deagglomerator outletport to the distal end of the first conduit, and

at least one second conduit for allowing air to flow from a proximal endof the adaptor to a distal end of the adaptor independently of theairflow in the first conduit when a breath induced low pressure isapplied to the distal end of the airflow adaptor,

and wherein the method comprises

testing the dry powder inhaler by means of a testing method described inany of the examples above; and

if necessary, adjusting the design by adjusting a ratio of the sum ofthe cross-sectional areas of the at least one second conduit to thecross-sectional area of the first conduit to thereby alter one or moregeometrical and/or dynamic characteristics of the dry powder plumedischarged from the inhaler upon application of a breath induced lowpressure to the distal end of the airflow adaptor.

The at least one second conduit changes the fluid dynamical propertiesof the consequently generated powder plume. In particular, it is to beexpected that by increasing the proportion of air flowing through the atleast one second conduit (i.e. the by-pass conduit), that the angle ofdeviation of the plume from horizontal may be decreased, and also thenarrowness and concentration of the plume may be increased.

The extent of this adjustment depends upon the number of second conduitsprovided and also their cross-sectional areas. In particular, themagnitude of the adjustment to the plume characteristics may be variedby altering the ratio of the aggregate cross-sectional areas of the atleast one second conduit to the cross-sectional area of the firstconduit. By varying this design feature, the characteristic of the plumecan be tuned.

In one embodiment the first dry powder inhaler 20 is a breath-actuateddry powder inhaler comprising an airflow adaptor 100, 200, 300, 50, 702,the airflow adaptor comprising:

a first conduit 101, 202, 302 having a proximal end and a distal end,wherein the proximal end allows fluid communication from adeagglomerator outlet port to the distal end of the first conduit, and

at least one second conduit 304, 305, 306 for allowing air to flow froma proximal end of the adaptor to a distal end of the adaptorindependently of the airflow in the first conduit 101, 202, 302 when abreath induced low pressure is applied to the distal end of the airflowadaptor,

and wherein the method comprises adjusting a ratio of the sum of thecross-sectional areas of the at least one second conduit 304, 305, 306to the cross-sectional area of the first conduit 101, 202, 302 so as toadjust vary one or more geometrical or dynamic characteristics of thedry powder plume discharged from the inhaler 20 upon application of abreath induced low pressure to the distal end of the airflow adaptor.

The present invention also provides a dry powder plume 24 generated bydischarge from a dry powder inhaler 20, characterised in that:

an angle of deviation of a central axis 42 of an outer envelope shape ofthe discharged plume 24 with respect to an axis of orientation of amouthpiece 22 of the inhaler is no greater than 8 degrees, and across-sectional area 44 of an outer envelope shape of the dischargedplume 24 at a distance of 3 cm from a source of discharge of the plumeis no greater than 5 cm².

Other variations to the disclosed embodiments can be understood andeffected by those skilled in the art in practising the claimedinvention, from a study of the drawings, the disclosure, and theappended claims. In the claims, the word “comprising” does not excludeother elements or steps, and the indefinite article “a” or “an” does notexclude a plurality. The mere fact that certain measures are recited inmutually different dependent claims does not indicate that a combinationof these measures cannot be used to advantage. Any reference signs inthe claims should not be construed as limiting the scope.

1. A method of testing a dry powder inhaler comprising the steps of:providing a dry powder inhaler containing a dry powder formulation;actuating the inhaler to discharge a dose of the dry powder formulationin the form of a dry powder plume; illuminating the plume with a sourceof electromagnetic radiation; capturing one or more images of a patternof radiation reflected or diffracted by the electromagneticallyilluminated plume; and processing the images to determine one or moregeometrical and/or dynamical characteristics of the discharged plume. 2.The method of claim 1, wherein the inhaler is actuated within a vacuumchamber or an air flow chamber.
 3. The method as of claim 1, wherein thesource of electromagnetic radiation comprises a source of visible light.4. The method of claim 1, wherein the source of electromagneticradiation is a laser.
 5. The method of claim 1, wherein the methodcomprises capturing a plurality of images in series.
 6. The method ofclaim 1, wherein an outer envelope shape of the discharged plume has acentral axis defining an angular orientation of the discharged plume,and wherein the method comprises analysing said angular orientation ofthe plume.
 7. The method of claim 6, wherein the dry powder inhalercomprises a mouthpiece, and wherein the method comprises determining anangle of deviation of said central axis of an outer envelope of thedischarged plume with respect to an axis of orientation of themouthpiece.
 8. The method of claim 1, wherein the method comprisesanalysing a cross-sectional area of an outer envelope shape of thedischarged plume at a given distance from a source of discharge of theplume.
 9. The method of claim 1, wherein the method comprisesdetermining a powder concentration distribution across a givencross-section of the discharged plume at a given distance from a sourceof discharge of the plume.
 10. A method of designing a dry powderinhaler, the inhaler being operable to discharge a dose of medicament inthe form of a dry powder plume, the method comprising: providing a firstdry powder inhaler in accordance with a first design, the designintended to achieve a particular desired set of plume geometric and/ordynamic characteristics; testing the dry powder inhaler by means of atesting method defined in claim 1; and if necessary, adjusting thedesign of the first dry powder inhaler based on results of said testingso as to better achieve the desired set of plume geometric and/ordynamic characteristics.
 11. The method of claim 10, wherein methodcomprises adjusting the design so as to minimise an angle of deviationof a central axis of an outer envelope shape of the discharged plumewith respect to an axis of orientation of a mouthpiece of the inhaler,and optionally wherein the mouthpiece defines a source of discharge ofthe plume.
 12. The method of claim 10, wherein the method comprisesadjusting the design so as to reduce a cross-sectional area of an outerenvelope shape of the discharged plume at a given distance from a sourceof discharge of the plume.
 13. The method of claim 10, wherein themethod comprises adjusting the design so as to alter a concentrationdistribution of the powder across a given cross-section of the plume,the cross-section being located at a given distance from a source ofdischarge of the plume.
 14. The method of claim 10, wherein the firstdry powder inhaler is a breath-actuated dry powder inhaler comprising anairflow adaptor, the airflow adaptor comprising: a first conduit havinga proximal end and a distal end, wherein the proximal end allows fluidcommunication from a deagglomerator outlet port to the distal end of thefirst conduit, and at least one second conduit for allowing air to flowfrom a proximal end of the adaptor to a distal end of the adaptorindependently of the airflow in the first conduit when a breath inducedlow pressure is applied to the distal end of the airflow adaptor, andwherein the method comprises adjusting a ratio of the sum of thecross-sectional areas of the at least one second conduit to thecross-sectional area of the first conduit so as to adjust vary one ormore geometrical or dynamic characteristics of the dry powder plumedischarged from the inhaler upon application of a breath induced lowpressure to the distal end of the airflow adaptor.
 15. A dry powderplume generated by discharge from a dry powder inhaler, characterised inthat: an angle of deviation of a central axis of an outer envelope shapeof the discharged plume with respect to an axis of orientation of amouthpiece of the inhaler is no greater than 8 degrees, and across-sectional area of an outer envelope shape of the discharged plumeat a distance of 3 cm from a source of discharge of the plume is nogreater than 5 cm².
 16. The method of claim 5, wherein the images arecaptured at regular intervals at an interval frequency of 300 Hz to1,000 Hz.
 17. The method of claim 8, wherein said source of thedischarge is defined as a distal end of a mouthpiece of the inhaler. 18.The method of claim 13, wherein the design is adjusted so as to increasea concentration of the powder within a central region of the crosssection, proximal to a central point of the cross section.